Lung cancer is one of the most common and deadly types of cancer (Sung et al., 2021). Presently, lung adenocarcinoma (LUAD) accounts for around 60% of newly diagnosed cases of lung cancer, making it the most prevalent subtype (Sung et al., 2021). The main forms of treatment for LUAD patients include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and immunotherapy (Allemani et al., 2018). However, the prognosis for LUAD patients is generally poor because of the fast growth of tumors and resistance to current treatments, with a 5-year survival rate of only about 30% (Lu et al., 2019). Investigating the regulatory mechanisms of tumor growth and therapy efficacy has thus become increasingly important.

Human transcription factors occupy a central role in all hallmarks of carcinogenesis, such as evading growth suppressors, resisting cell death, and deregulating cellular metabolism by regulating gene transcriptions (Hanahan, 2022, Konstantinopoulos and Papavassiliou, 2011). Several agents targeting transcription factors, such as RARa activator SY-1425 (McKeown et al., 2019) and MYC inhibitor OMO-103 (Direct, 2022), have been evaluated in clinical trials and have shown potential efficacy in cancer treatment. There are hundreds of transcription factors, but many of their functions and potentials in cancer treatment are unclear.

In this study, we demonstrated that MAF BZIP Transcription Factor F (MAFF) strongly suppressed the proliferation of LUAD in vitro and in vivo. We identified that MAFF was downregulated in cisplatin-resistant cells and clinical cases of cisplatin-refractory tumors. We showed that SLC7A11, CDK6, and CDKN2C, are three of the principal downstream genes of MAFF, triggering ferroptosis and halting the cell cycle at the G1 phase. Most importantly, results from 3D cell culture system and murine xenograft models validated the inhibitory function of MAFF in carcinogenesis and the benefit of boosting cancer treatments. Taken together, we provided basic mechanistic insight into the role of MAFF and implicated it as a promising therapeutic booster for cancer treatments in LUAD.